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Cardiac biomarkers in equine medicine
The Veterinary Journal 192 (2012) 131–132
Contents lists available at SciVerse ScienceDirect
The Veterinary Journal journal homepage: www.elsevier.com/locate/tvjl
Guest Editorial
Cardiac biomarkers in equine medicine
Biomarkers are distinctive biological indicators of processes, events, or conditions occurring within the body. They can indicate physiological processes (such as growth and aging), or pathophysiological processes that occur with disease (e.g. cardiac damage, heart failure). As such, biomarkers can aid in the diagnosis and prognosis of diseases within individuals. Biomarkers can be sub-divided into leakage enzymes and functional markers. The former are released from damaged cells, whereas the latter increase or decrease in response to a biological process or disease. Non-cardiac biomarkers have been used in equine medicine for decades to assess multiple organ systems. Examples include alanine transaminase (ALT) as a leakage enzyme for hepatic cells and creatinine as a functional marker for renal disease. It is only recently that biomarkers for cardiac disease have been evaluated in equine medicine. The most studied cardiac biomarkers in any species include the troponins (which are leakage enzymes) and the natriuretic peptides atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) (which are functional markers). In human medicine, cardiac troponin has been shown to be both highly sensitive and specific for cardiomyocyte damage (Baker et al., 2011). Cardiac troponin I (cTnI) has appeared in the equine literature for the last decade, during which time there have been multiple case reports of horses with cardiac damage having high concentrations of cardiac troponin. There have been two prospective studies showing that cardiac troponin increases with induced cardiac necrosis in horses, and that the increase appears to be positively associated with the degree of cardiac damage at necropsy (Divers et al., 2009; Kraus et al., 2010). Because of cardiac troponin’s sensitivity and specificity, it has also been used as a biomarker for cardiac damage associated with therapeutic interventions, such as transvenous electrical cardioversion for atrial fibrillation (Jesty et al., 2009). Additionally, there has been investigation into its usefulness as a marker for cardiac dysfunction in horses with poor performance. Studies have shown that cTnI can increase in some exercising horses, although generally the increase is mild and can occur in horses performing normally as well as those with poor performance (Holbrooke et al., 2006; Nostell and Haggstrom, 2008). The assessment of the ability of cardiac troponins to indicate subtle cardiac disease in poor performing horses is hampered by the lack of a gold standard for assessing cardiac damage in horses, and by our incomplete understanding thus far of the effect of strenuous exercise on the concentration of troponin in normal horses. Despite the sensitivity and specificity of the troponins for cardiomyocyte necrosis, they have not proven very useful in diagnosing heart failure, or indeed many heart diseases, in veterinary medicine. This is likely because most cardiac diseases in animals do not cause significant cardiomyocyte necrosis and, therefore, the troponins would not be expected to increase. To evaluate heart 1090-0233/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tvjl.2011.11.011
disease that does not induce cardiomyocyte necrosis, one needs a functional biomarker that increases as atrial and ventricular remodeling occurs; this biomarker would then be expected to increase with various heart diseases and heart failure. The natriuretic peptides are just such cardiac biomarkers. ANP is synthesized in the atria and BNP in the ventricles and atria in response to myocardial stretch, volume, or pressure overload, which occur in many chronic heart diseases prior to the advent of obvious heart failure. In people, ANP and BNP are used to predict heart disease severity, to predict mortality, to monitor treatment, and to identify patients with asymptomatic dysfunction. During release, proANP and proBNP are cleaved into the biologically active C-terminal fragments and the biologically inactive N-terminal fragments. Either fragment may be a target for testing, but most tests assess the NT fragments because they are more stable with longer half-lives. The report by Dr. Dagmar Trachsel of the VetSuisse Faculty of the University of Zurich, and her colleagues, published in the current edition of The Veterinary Journal is the first to correlate NT-proANP concentration with left atrial size in horses with heart disease (Trachsel et al., 2012), while a previous paper showed a non-statistically significant trend of increasing ANP with heart disease in horses (Gehlen et al., 2007). In dogs and cats, NT-proANP and NTproBNP can help differentiate animals with dyspnea from heart failure from animals with dyspnea from extracardiac causes (Prosek et al., 2007; Zimmering et al., 2009). Additionally, the natriuretic peptides have been shown to have some ability to distinguish between animals with occult disease and animals without disease; their performance for this being much better in cats (Chetboul et al., 2009; Zimmering et al., 2009). The natriuretic peptides’ ability to screen for subclinical heart disease (usually valve disease) in horses and the ability to discriminate dyspnea caused by heart failure from dyspnea caused by other diseases has yet to be fully determined, but the paper by Trachsel et al. (2012) certainly paves the way for further investigation. Included in future research should be the effect of other disease processes (such as azotemia) on the concentrations of cTnI and the natriuretic peptides, and the evaluation of other cardiac biomarkers. Not only might multiple other proteins and enzymes prove useful, but also the differential expression levels of various cardiac related genes could prove useful as cardiac biomarkers. Biomarkers are tempting diagnostic tests because they are often blood tests, and, as such, are easily collected and do not require significant expertise for interpretation. As more is published in the equine literature on the use of cardiac biomarkers, I have no doubt that they will be used as an aid in the diagnosis and prognosis of heart disease in horses. The ideal biomarker would detect subtle disease, diagnose chronic or acute disease syndromes, stratify patient
132
Guest Editorial / The Veterinary Journal 192 (2012) 131–132
risk, and accurately monitor disease progression or response to treatment. At the moment, a perfect biomarker with high sensitivity and specificity for all heart conditions does not exist in any species and I do not believe that biomarkers will ever replace the need for additional cardiac testing, such as echocardiography, radiography, and electrocardiography. But if cardiac biomarkers can increase the sensitivity to diagnose heart disease, improve our ability to differentiate heart failure from other causes of dyspnea, identify cardiac dysfunction in poor performing horses, or help formulate an accurate prognosis and monitor the effects of therapy, they will play as important a role in equine medicine as they do in other species. Sophy A. Jesty Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Tennessee, 2407 River Drive, Knoxville, TN 37996, USA E-mail address: [email protected]
References Baker, J.O., Reinhold, J., Redwood, S., Marber, M.S., 2011. Troponins: Redefining their limits. Heart 9, 447–452.
Chetboul, V., Serres, F., Tissier, R., Lefebvre, H.P., Sampedrano, C.C., Gouni, V., Poujol, L., Hawa, G., Pouchelon, J.L., 2009. Association of plasma N-terminal Pro-B-type natriuretic peptide concentration with mitral regurgitation severity and outcome in dogs with asymptomatic degenerative mitral valve disease. Journal of Veterinary Internal Medicine 23, 984–994. Divers, T.J., Kraus, M.S., Jesty, S.A., Miller, A.D., Mohammed, H.O., Gelzer, A.R., Mitchell, L.M., Soderholm, L.V., Ducharme, N.G., 2009. Clinical findings and serum cardiac troponin I concentrations in horses after intragastric administration of sodium monensin. Journal of Veterinary Diagnostic Investigations 21, 338–343. Gehlen, H., Sundermann, T., Rohn, K., Stadler, P., 2007. Plasma atrial natriuretic peptide concentration in Warmblood horses with heart valve regurgitations. Journal of Veterinary Cardiology 9, 99–101. Holbrooke, T.C., Birks, E.K., Sleeper, M.M., Durando, M., 2006. Endurance exercise is associated with increased plasma troponin I in horses. Equine Veterinary Journal Supp. 36, 27–31. Jesty, S.A., Kraus, M.S., Gelzer, A.R., Rishniw, M., Moise, N.S., 2009. Effect of transvenous electrical cardioversion on plasma cardiac troponin I concentrations in horses with atrial fibrillation. Journal of Veterinary Internal Medicine 23, 1103–1107. Kraus, M.S., Jesty, S.A., Gelzer, A.R., Ducharme, N.G., Mohammed, H.O., Mitchell, L.M., Soderholm, L.V., Divers, T.J., 2010. Measurements of plasma cardiac troponin I concentration by use of a point-of-care analyzer in clinically normal horses and horses with experimentally induced cardiac disease. American Journal of Veterinary Research 71, 55–59. Nostell, K., Haggstrom, J., 2008. Resting concentrations of cardiac troponin I in fit horses and effect of racing. Journal of Veterinary Cardiology 10, 105–109. Prosek, R., Sisson, D.D., Oyama, M.A., Solter, P.F., 2007. Distinguishing cardiac and noncardiac dyspnea in 48 dogs using plasma atrial natriuretic factor, B-type natriuretic factor, endothelin, and cardiac troponin-I. Journal of Veterinary Internal Medicine 21, 238–242. Trachsel, D.S., Grenacher, B., Weishaupt, M.A., Schwarzwald, C.C., 2012. Plasma atrial natriuretic peptide concentrations in horses with heart disease: A pilot study. The Veterinary Journal. 192, 166–170. Zimmering, T.M., Meneses, F., Nolte, I.J., Simon, D., 2009. Measurement of Nterminal proatrial natriuretic peptide in plasma of cats with and without cardiomyopathy. American Journal of Veterinary Research 70, 216–222.
Contents lists available at SciVerse ScienceDirect
The Veterinary Journal journal homepage: www.elsevier.com/locate/tvjl
Guest Editorial
Cardiac biomarkers in equine medicine
Biomarkers are distinctive biological indicators of processes, events, or conditions occurring within the body. They can indicate physiological processes (such as growth and aging), or pathophysiological processes that occur with disease (e.g. cardiac damage, heart failure). As such, biomarkers can aid in the diagnosis and prognosis of diseases within individuals. Biomarkers can be sub-divided into leakage enzymes and functional markers. The former are released from damaged cells, whereas the latter increase or decrease in response to a biological process or disease. Non-cardiac biomarkers have been used in equine medicine for decades to assess multiple organ systems. Examples include alanine transaminase (ALT) as a leakage enzyme for hepatic cells and creatinine as a functional marker for renal disease. It is only recently that biomarkers for cardiac disease have been evaluated in equine medicine. The most studied cardiac biomarkers in any species include the troponins (which are leakage enzymes) and the natriuretic peptides atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) (which are functional markers). In human medicine, cardiac troponin has been shown to be both highly sensitive and specific for cardiomyocyte damage (Baker et al., 2011). Cardiac troponin I (cTnI) has appeared in the equine literature for the last decade, during which time there have been multiple case reports of horses with cardiac damage having high concentrations of cardiac troponin. There have been two prospective studies showing that cardiac troponin increases with induced cardiac necrosis in horses, and that the increase appears to be positively associated with the degree of cardiac damage at necropsy (Divers et al., 2009; Kraus et al., 2010). Because of cardiac troponin’s sensitivity and specificity, it has also been used as a biomarker for cardiac damage associated with therapeutic interventions, such as transvenous electrical cardioversion for atrial fibrillation (Jesty et al., 2009). Additionally, there has been investigation into its usefulness as a marker for cardiac dysfunction in horses with poor performance. Studies have shown that cTnI can increase in some exercising horses, although generally the increase is mild and can occur in horses performing normally as well as those with poor performance (Holbrooke et al., 2006; Nostell and Haggstrom, 2008). The assessment of the ability of cardiac troponins to indicate subtle cardiac disease in poor performing horses is hampered by the lack of a gold standard for assessing cardiac damage in horses, and by our incomplete understanding thus far of the effect of strenuous exercise on the concentration of troponin in normal horses. Despite the sensitivity and specificity of the troponins for cardiomyocyte necrosis, they have not proven very useful in diagnosing heart failure, or indeed many heart diseases, in veterinary medicine. This is likely because most cardiac diseases in animals do not cause significant cardiomyocyte necrosis and, therefore, the troponins would not be expected to increase. To evaluate heart 1090-0233/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tvjl.2011.11.011
disease that does not induce cardiomyocyte necrosis, one needs a functional biomarker that increases as atrial and ventricular remodeling occurs; this biomarker would then be expected to increase with various heart diseases and heart failure. The natriuretic peptides are just such cardiac biomarkers. ANP is synthesized in the atria and BNP in the ventricles and atria in response to myocardial stretch, volume, or pressure overload, which occur in many chronic heart diseases prior to the advent of obvious heart failure. In people, ANP and BNP are used to predict heart disease severity, to predict mortality, to monitor treatment, and to identify patients with asymptomatic dysfunction. During release, proANP and proBNP are cleaved into the biologically active C-terminal fragments and the biologically inactive N-terminal fragments. Either fragment may be a target for testing, but most tests assess the NT fragments because they are more stable with longer half-lives. The report by Dr. Dagmar Trachsel of the VetSuisse Faculty of the University of Zurich, and her colleagues, published in the current edition of The Veterinary Journal is the first to correlate NT-proANP concentration with left atrial size in horses with heart disease (Trachsel et al., 2012), while a previous paper showed a non-statistically significant trend of increasing ANP with heart disease in horses (Gehlen et al., 2007). In dogs and cats, NT-proANP and NTproBNP can help differentiate animals with dyspnea from heart failure from animals with dyspnea from extracardiac causes (Prosek et al., 2007; Zimmering et al., 2009). Additionally, the natriuretic peptides have been shown to have some ability to distinguish between animals with occult disease and animals without disease; their performance for this being much better in cats (Chetboul et al., 2009; Zimmering et al., 2009). The natriuretic peptides’ ability to screen for subclinical heart disease (usually valve disease) in horses and the ability to discriminate dyspnea caused by heart failure from dyspnea caused by other diseases has yet to be fully determined, but the paper by Trachsel et al. (2012) certainly paves the way for further investigation. Included in future research should be the effect of other disease processes (such as azotemia) on the concentrations of cTnI and the natriuretic peptides, and the evaluation of other cardiac biomarkers. Not only might multiple other proteins and enzymes prove useful, but also the differential expression levels of various cardiac related genes could prove useful as cardiac biomarkers. Biomarkers are tempting diagnostic tests because they are often blood tests, and, as such, are easily collected and do not require significant expertise for interpretation. As more is published in the equine literature on the use of cardiac biomarkers, I have no doubt that they will be used as an aid in the diagnosis and prognosis of heart disease in horses. The ideal biomarker would detect subtle disease, diagnose chronic or acute disease syndromes, stratify patient
132
Guest Editorial / The Veterinary Journal 192 (2012) 131–132
risk, and accurately monitor disease progression or response to treatment. At the moment, a perfect biomarker with high sensitivity and specificity for all heart conditions does not exist in any species and I do not believe that biomarkers will ever replace the need for additional cardiac testing, such as echocardiography, radiography, and electrocardiography. But if cardiac biomarkers can increase the sensitivity to diagnose heart disease, improve our ability to differentiate heart failure from other causes of dyspnea, identify cardiac dysfunction in poor performing horses, or help formulate an accurate prognosis and monitor the effects of therapy, they will play as important a role in equine medicine as they do in other species. Sophy A. Jesty Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Tennessee, 2407 River Drive, Knoxville, TN 37996, USA E-mail address: [email protected]
References Baker, J.O., Reinhold, J., Redwood, S., Marber, M.S., 2011. Troponins: Redefining their limits. Heart 9, 447–452.
Chetboul, V., Serres, F., Tissier, R., Lefebvre, H.P., Sampedrano, C.C., Gouni, V., Poujol, L., Hawa, G., Pouchelon, J.L., 2009. Association of plasma N-terminal Pro-B-type natriuretic peptide concentration with mitral regurgitation severity and outcome in dogs with asymptomatic degenerative mitral valve disease. Journal of Veterinary Internal Medicine 23, 984–994. Divers, T.J., Kraus, M.S., Jesty, S.A., Miller, A.D., Mohammed, H.O., Gelzer, A.R., Mitchell, L.M., Soderholm, L.V., Ducharme, N.G., 2009. Clinical findings and serum cardiac troponin I concentrations in horses after intragastric administration of sodium monensin. Journal of Veterinary Diagnostic Investigations 21, 338–343. Gehlen, H., Sundermann, T., Rohn, K., Stadler, P., 2007. Plasma atrial natriuretic peptide concentration in Warmblood horses with heart valve regurgitations. Journal of Veterinary Cardiology 9, 99–101. Holbrooke, T.C., Birks, E.K., Sleeper, M.M., Durando, M., 2006. Endurance exercise is associated with increased plasma troponin I in horses. Equine Veterinary Journal Supp. 36, 27–31. Jesty, S.A., Kraus, M.S., Gelzer, A.R., Rishniw, M., Moise, N.S., 2009. Effect of transvenous electrical cardioversion on plasma cardiac troponin I concentrations in horses with atrial fibrillation. Journal of Veterinary Internal Medicine 23, 1103–1107. Kraus, M.S., Jesty, S.A., Gelzer, A.R., Ducharme, N.G., Mohammed, H.O., Mitchell, L.M., Soderholm, L.V., Divers, T.J., 2010. Measurements of plasma cardiac troponin I concentration by use of a point-of-care analyzer in clinically normal horses and horses with experimentally induced cardiac disease. American Journal of Veterinary Research 71, 55–59. Nostell, K., Haggstrom, J., 2008. Resting concentrations of cardiac troponin I in fit horses and effect of racing. Journal of Veterinary Cardiology 10, 105–109. Prosek, R., Sisson, D.D., Oyama, M.A., Solter, P.F., 2007. Distinguishing cardiac and noncardiac dyspnea in 48 dogs using plasma atrial natriuretic factor, B-type natriuretic factor, endothelin, and cardiac troponin-I. Journal of Veterinary Internal Medicine 21, 238–242. Trachsel, D.S., Grenacher, B., Weishaupt, M.A., Schwarzwald, C.C., 2012. Plasma atrial natriuretic peptide concentrations in horses with heart disease: A pilot study. The Veterinary Journal. 192, 166–170. Zimmering, T.M., Meneses, F., Nolte, I.J., Simon, D., 2009. Measurement of Nterminal proatrial natriuretic peptide in plasma of cats with and without cardiomyopathy. American Journal of Veterinary Research 70, 216–222.